Lowered-intensity preparative regimen for allogeneic stem cell transplantation delays acute graft-versus-host disease but does not improve outcome for advanced hematologic malignancy

AbstractReduced conditioning intensity has extended the option of allogeneic hematopoietic stem cell transplantation to patients who cannot tolerate fully myeloablative regimens. However, relapse and graft-versus-host disease (GVHD) continue to be major causes of morbidity and mortality. We prospectively tested whether a moderate reduction of the intensity of the preparative regimen would lead to significant reduction in regimen-related toxicity without compromising tumor control in a cohort of 44 patients ineligible for conventional hematopoietic stem cell transplantation. Patients were conditioned with fludarabine, busulfan, mycophenolate, and total lymphoid irradiation. Tacrolimus and methotrexate were given as prophylaxis for GVHD. Donors were 5 of 6 or 6 of 6 matched family members. The median age was 61 years. Eleven patients had comorbid conditions that precluded conventional myeloablative transplantation. Fatal regimen-related organ toxicity occurred in 3 patients. The cumulative incidence of grade 2 to 4 or grade 3 to 4 acute GVHD by day 100 was 38% (95% confidence interval [CI] = 25%, 55%) and 20% (95% CI = 10%, 39%), respectively, with a median time to onset of 66 days. For the entire cohort, 1-year overall survival, disease-free survival, and relapse rates were 54% (95% CI = 41%, 71%), 47% (95% CI = 35%, 65%), and 37% (95% CI = 19%, 51%), respectively. Outcomes differed based on stage of disease at time of transplantation, advanced (n = 19) versus nonadvanced (n = 25). Median survival times were 138 days and 685 days for subjects with advanced and nonadvanced disease, respectively (P = .005). After adjusting for age and comorbidity, disease stage continued to be significantly associated with overall survival (P = .005). In conclusion, a moderate reduction in conditioning dose intensity resulted in delayed onset of acute GVHD (compared with historical controls). A reduction in conditioning intensity is associated with poor survival for patients with advanced-stage disease, highlighting the importance of the conditioning regimen for tumor control. © 2003 American Society for Blood and Marrow TransplantationBiology of Blood and Marrow Transplantation 9:189-197 (2003

Are any coastal internal tides predictable?

Author Posting. © The Oceanography Society, 2012. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 25, No. 2 (2012): 80-95, doi:10.5670/oceanog.2012.44.Surface tides are the heartbeat of the ocean. Because they are controlled by Earth's motion relative to other astronomical objects in our solar system, surface tides act like clockwork and generate highly deterministic ebb and flow familiar to all mariners. In contrast, baroclinic motions at tidal frequencies are much more stochastic, owing to complexities in how these internal motions are generated and propagate. Here, we present analysis of current records from continental margins worldwide to illustrate that coastal internal tides are largely unpredictable. This conclusion has numerous implications for coastal processes, as across-shelf exchange and vertical mixing are, in many cases, strongly influenced by the internal wave field.This work was supported through grants from the US Office of Naval Research and NSF (Nash, Shroyer, Musgrave, Levine, and Duda), by NERC (grant NE/IO30224/1 FASTNEt; Inall), and by AIMS/CSIRO (Kelly and Jones)

A surface groove essential for viral Bcl-2 function during chronic infection in vivo

Antiapoptotic Bcl-2 family proteins inhibit apoptosis in cultured cells by binding BH3 domains of proapoptotic Bcl-2 family members via a hydrophobic BH3 binding groove on the protein surface. We investigated the physiological importance of the BH3 binding groove of an antiapoptotic Bcl-2 protein in mammals in vivo by analyzing a viral Bcl-2 family protein. We show that the gamma-herpesvirus 68 (gammaHV68) Bcl-2 family protein (gammaHV68 v-Bcl-2), which is known to inhibit apoptosis in cultured cells, inhibits both apoptosis in primary lymphocytes and Bax toxicity in yeast. Nuclear magnetic resonance determination of the gammaHV68 v-Bcl-2 structure revealed a BH3 binding groove that binds BH3 domain peptides from proapoptotic Bcl-2 family members Bax and Bak via a molecular mechanism shared with host Bcl-2 family proteins, involving a conserved arginine in the BH3 peptide binding groove. Mutations of this conserved arginine and two adjacent amino acids to alanine (SGR to AAA) within the BH3 binding groove resulted in a properly folded protein that lacked the capacity of the wild-type gammaHV68 v-Bcl-2 to bind Bax BH3 peptide and to block Bax toxicity in yeast. We tested the physiological importance of this v-Bcl-2 domain during viral infection by engineering viral mutants encoding a v-Bcl-2 containing the SGR to AAA mutation. This mutation resulted in a virus defective for both efficient reactivation of gammaHV68 from latency and efficient persistent gammaHV68 replication. These studies demonstrate an essential functional role for amino acids in the BH3 peptide binding groove of a viral Bcl-2 family member during chronic infection

Disparities in registration and use of an online patient portal among older adults: findings from the LitCog cohort

(C) The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved.Financial disclosure: This project was supported by the National Institute on Aging (R01 AG030611), the National Center for Research Resources (5UL1RR025741), and the National Center for Advancing Translational Sciences (Grant 8UL1TR000150). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Smith is currently supported by a Cancer Research UK Fellowship

'Tough'-constructions and their derivation

This article addresses the syntax of the notorious 'tough' (-movement) construction (TC) in English. TCs exhibit a range of apparently contradictory empirical properties suggesting that their derivation involves the application of both A-movement and A'-movement operations. Given that within previous Principles and Parameters models TCs have remained “unexplained and in principle unexplainable” (Holmberg 2000: 839) due to incompatibility with constraints on theta-assignment, locality, and Case, this article argues that the phase-based implementation of the Minimalist program (Chomsky 2000, 2001, 2004) permits a reanalysis of null wh-operators capable of circumventing the previous theoretical difficulties. Essentially, 'tough'-movement consists of A-moving a constituent out of a “complex” null operator which has already undergone A'-movement, a “smuggling” construction in the terms of Collins (2005a,b

High-energy neutrino conversion and the lepton asymmetry in the universe

We study matter effects on oscillations of high-energy neutrinos in the Universe. Substantial effect can be produced by scattering of the neutrinos from cosmological sources (z\gta 1) on the relic neutrino background, provided that the latter has large CP-asymmetry: \eta\equiv (n_\nu-n_{\bar{\nu}})/n_\gamma\gta 1, where $n_\nu$, $n_{\bar{\nu}}$ and $n_\gamma$ are the concentrations of neutrinos, antineutrinos and photons. We consider in details the dynamics of conversion in the expanding neutrino background. Applications are given to the diffuse fluxes of neutrinos from GRBs, AGN, and the decay of super-heavy relics. We find that the vacuum oscillation probability can be modified by $\sim (10-20)$ and in extreme cases allowed by present bounds on $\eta$ the effect can reach $\sim 100$. Signatures of matter effects would consist (i) for both active-active and active-sterile conversion, in a deviation of the numbers of events produced in a detector by neutrinos of different flavours, $N_{\alpha}~(\alpha=e,\mu,\tau)$, and of their ratios from the values given by vacuum oscillations; such deviations can reach $\sim 5-15$, (ii) for active-sterile conversion, in a characteristic energy dependence of the ratios $N_{e}/N_{\mu},N_{e}/N_{\tau},N_{\mu}/N_{\tau}$. Searches for these matter effects will probe large CP and lepton asymmetries in the universe.Comment: 32 pages, RevTeX, 16 figures. Substantial changes in the treatment of conversion effects in the relic neutrino background and of active-active oscillations of high-energy neutrinos. Figures and references added; conclusions partially modifie

The Standard Model Prediction of the Muon Anomalous Magnetic Moment

This article reviews and updates the Standard Model prediction of the muon g-2. QED, electroweak and hadronic contributions are presented, and open questions discussed. The theoretical prediction deviates from the present experimental value by 2-3 standard deviations, if e+e- annihilation data are used to evaluate the leading hadronic term.Comment: 30 pages, 8 figures. v2: Updated version to appear in J.Phys.G. Comments and references added, typo corrected in eq.(17

TESS Discovery of a Transiting Super-Earth in the π\pi Mensae System

We report the detection of a transiting planet around $\pi$ Mensae (HD 39091), using data from the Transiting Exoplanet Survey Satellite (TESS). The solar-type host star is unusually bright (V=5.7) and was already known to host a Jovian planet on a highly eccentric, 5.7-year orbit. The newly discovered planet has a size of $2.04\pm 0.05$ $R_\oplus$ and an orbital period of 6.27 days. Radial-velocity data from the HARPS and AAT/UCLES archives also displays a 6.27-day periodicity, confirming the existence of the planet and leading to a mass determination of $4.82\pm 0.85$ $M_\oplus$. The star's proximity and brightness will facilitate further investigations, such as atmospheric spectroscopy, asteroseismology, the Rossiter--McLaughlin effect, astrometry, and direct imaging.Comment: Accepted for publication ApJ Letters. This letter makes use of the TESS Alert data, which is currently in a beta test phase. The discovery light curve is included in a table inside the arxiv submissio

Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis

PMCID: PMC379391